The main goals of this research are to investigate the in vivo immunomodulatory effects of a) acute ethanol exposure alone and b)the combined immunosuppressive potential of alcohol uptake and trauma in humans. Immunosuppressive effects of chronic alcohol use have been reported by a number of investigators. Our data and that of others also demonstrate immunoinhibitory potential of acute ethanol exposure resulting in decreased anti-bacterial defense, depressed inflammatory cytokine production, and altered T cell activation. All of these immune abnormalities could be linked to aberrant monocyte functions found after in vitro acute ethanol exposure. We identified aberrant accessory cell function, decreased pro-inflammatory monokine, and increased inhibitory mediator production in acute ethanol exposed monocyte. We also showed that decreased antigen-specific T cell proliferation after acute ethanol exposure is due to impaired monocyte antigen presenting function, and involves aberrant production of monocyte-derived T cell stimulatory mediators.Consequently, we hypothesize that acute ethanol exposure affects the immune system by altering monocyte accessory capacity, cytokine production, and expression of surface antigens/receptors involved in monocyte-T cell interactions. Aberrant monocyte functions after acute ethanol use would then contribute to impaired T and B lymphocyte, and NK cell functions. Monocyte also play a pivotal role in mediation of post- trauma immunosuppression. Acute ethanol exposure has been shown to increase post-trauma immunosuppression in mice. Our human data also indicate that acute ethanol uptake prior to injury can alter monokine production contributing to post-trauma immunosuppression. Therefore, we further hypothesize that acute ethanol exposure can increase post-trauma immunosuppression via affecting monocyte. These hypotheses will be tested by evaluating the effect of acute in vivo uptake on monocyte functions in normals and in three trauma patient groups: non-alcoholic, alcohol uptake prior to trauma without chronic use, and chronic alcoholic patients. The effects of ethanol alone or with trauma on monocyte-induced aberrant T cell activation will be evaluated in three systems: tetanus toxoid antigen proliferation, superantigen- and mitogen-induced T cell proliferation, each requiring different degrees of monocyte participation. The immunosuppressive role of monocyte derived pro-inflammatory cytokines(TNFalpha, IL-1, IL-6) and inhibitory mediators(TGFbeta ,PGE2, IL-10) will be evaluated by correlating the levels of these cytokines to abnormal monocyte accessory function after acute ethanol exposure alone or with trauma. We will test ethanol-induced mechanisms modulating monocyte susceptibility to subsequent stimulation(bacterial or trauma) by correlating cytokine protein and mRNA levels. Ethanol plus trauma-induced aberrations in monocyte surface antigens/receptor expression(HLA- DR,B7,IFNgammaR), leading to altered monocyte-T cell interactions or monocyte autoregulation, will be identified. We will also test if ethanol alone or with trauma results in a preferential induction or altered function of monocyte subpopulations identified on the basis of surface Fc- gammaRI, CD4, CD33+CD14(dim) expression. Finally, the effects of ethanol plus trauma-induced aberrant monocyte mediator environment affects will be assayed on monocyte differentiation. These experiments will define monocyte alterations leading to the combined immunosuppressive effects of in vivo ethanol uptake and trauma.